LCK facilitates DNA damage repair by stabilizing RAD51 and BRCA1 in the nucleus of chemoresistant ovarian cancer.

Poly-ADP Ribose Polymerase (PARP) targeted therapy is clinically approved for the treatment of homologous recombination (HR) repair deficient tumors. The remarkable success of this therapy in the treatment of HR repair deficient cancers has not translated to HR-proficient cancers. Our studies identify the novel role of non-receptor lymphocyte-specific protein tyrosine kinase (LCK) in the regulation of HR repair in endometrioid epithelial ovarian cancer (eEOC) model. We show that DNA damage leads to direct interaction of LCK with the HR repair proteins RAD51 and BRCA1 in a kinase dependent manner RAD51 and BRCA1 stabilization. LCK expression is induced and activated in the nucleus in response to DNA damage insult. Disruption of LCK expression attenuates RAD51, BRCA1, and BRCA2 protein expression by hampering there stability and results in inhibition of HR-mediated DNA repair including suppression of RAD51 foci formation, and augmentation of γH2AX foci formation. In contrast LCK overexpression leads to increased RAD51 and BRCA1 expression with a concomitant increase in HR DNA damage repair. Importantly, attenuation of LCK sensitizes HR-proficient eEOC cells to PARP inhibitor in cells and pre-clinical mouse studies. Collectively, our findings identify a novel therapeutic strategy to expand the utility of PARP targeted therapy in HR proficient ovarian cancer.

Pretreatment with LCK inhibitors chemosensitizes cisplatin-resistant endometrioid ovarian tumors.

BACKGROUND: Ovarian cancer is the most fatal gynecologic malignancy in the United States. While chemotherapy is effective in the vast majority of ovarian cancer patients, recurrence and resistance to standard systemic therapy is nearly inevitable. We discovered that activation of the non-receptor tyrosine kinase Lymphocyte Cell-Specific Protein-Tyrosine Kinase (LCK) promoted cisplatin resistance. Here, we hypothesized that treating high grade, platinum resistant endometrioid cancer cells with an LCK inhibitor (LCKi) followed by co-treatment with cisplatin would lead to increased cisplatin efficacy. Our objective was to assess clinical outcomes associated with increased LCK expression, test our hypothesis of utilizing LCKi as pre-treatment followed by co-treatment with cisplatin in platinum resistant ovarian cancer in vitro, and evaluate our findings in vivo to assess LCKi applicability as a therapeutic agent. RESULTS: Kaplan-Meier (KM) plotter data indicated LCK expression is associated with significantly worse median progression-free survival (HR 3.19, p = 0.02), and a trend toward decreased overall survival in endometrioid ovarian tumors with elevated LCK expression (HR 2.45, p = 0.41). In vitro, cisplatin resistant ovarian endometrioid cells treated first with LCKi followed by combination LCKi-cisplatin treatment showed decreased cell viability and increased apoptosis. Immunoblot studies revealed LCKi led to increased expression of phosphorylated H2A histone family X ([Formula: see text]-H2AX), a marker for DNA damage. In vivo results demonstrate treatment with LCKi followed by LCKi-cisplatin led to significantly slowed tumor growth. CONCLUSIONS: We identified a strategy to therapeutically target cisplatin resistant endometrioid ovarian cancer leading to chemosensitization to platinum chemotherapy via treatment with LCKi followed by co-treatment with LCKi-cisplatin.

Fertility-Sparing Surgery for Early-Stage Cervical Cancer: A Systematic Review of the Literature.

OBJECTIVE: This systematic review aimed to evaluate oncologic and reproductive outcomes after fertility-sparing surgery (FSS) for early-stage cervical cancer (early CC). DATA SOURCES: Ovid MEDLINE, Ovid EMBASE, and Cochrane CENTRAL were searched from 1980 to the present using Medical Subject Headings terms; other controlled vocabulary terms; and keywords related to fertility, cervical cancer, and surgical techniques. METHODS OF STUDY SELECTION: A total of 2415 studies were screened, with 53 studies included. Studies reporting recurrences with a median follow-up of 12 months in early CC (International Federation of Gynecology and Obstetrics 2009 stages IA with lymphovascular space invasion, IB, or IIA) of traditional histologic type undergoing FSS were included. TABULATION, INTEGRATION, AND RESULTS: The studies were grouped by intervention, including vaginal radical trachelectomy (VRT), abdominal radical trachelectomy (ART), minimally invasive radical trachelectomy (MIS-RT), and conization or simple trachelectomy (ST), and studies involving neoadjuvant chemotherapy (NACT). Combined rates of recurrence (RR), cancer death (CDR), pregnancy (PR), and live birth (LBR) were calculated per procedure on the basis of all included studies that reported outcomes on that procedure. The results were as follows: VRT: RR 4%, CDR 1.7%, PR 49.4%, and LBR 65.0% ART: RR 3.9%, CDR 1.4%, PR 43.2%, and LBR 44.0% MIS-RT: RR 4.2%, CDR 0.7%, PR 36.2%, and LBR 57.1% Cone or ST: RR 4.2%, CDR 0.8%, PR 55.1%, and LBR 71.9% NACT: RR 7.5% and CDR 2.0% CONCLUSION: FSS of early CC with VRT, ART, or MIS-RT have comparable oncologic outcomes in carefully selected patients, with reproductive outcomes favoring VRT. Data on nonradical FSS with cone or ST are less robust but support similar oncologic outcomes to radical trachelectomy with fewer reproductive complications. NACT in this setting requires more investigation before routine implementation into practice.

A guide to establishing a hyperthermic intraperitoneal chemotherapy program in gynecologic oncology.

Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) may be used to treat peritoneal based malignancies, such as epithelial ovarian cancer (EOC). Despite results of clinical trials supporting an increasing indication for HIPEC in EOC, concerns have existed regarding morbidity and challenges with initiating HIPEC at an institutional level. The objective of this review is to describe evidence-based recommendations to guide implementation of a HIPEC program, following our experience at a high-volume tertiary care center. Establishing a HIPEC program requires building a multi-disciplinary team, including gynecologic oncologists, anesthesia, nursing, perfusionists and pharmacists. Team members require education regarding HIPEC protocols, toxic waste and spill management, and personal protective equipment (PPE). Required equipment includes chemotherapy certified PPE and a HIPEC pump which is connected to inflow and outflow catheters placed within the peritoneal cavity. During the procedure, 3-6 L of a hyperthermic perfusate, composed of a isotonic crystalloid vehicle and the chemotherapy of choice, is infused through the peritoneal cavity with goal temperature of 41-43 °C. Prior to HIPEC infusion, surgical teams must communicate with anesthesia and pharmacy. In patients receiving HIPEC with cisplatin, furosemide and mannitol should be administered one hour prior to chemotherapy to ensure adequate diuresis. Sodium thiosulfate may also be considered for renal protection (van Driel et al., n.d. [3]). We utilize a multi-agent pre-medication protocol prior to HIPEC infusion to reduce hypersensitivity reactions, renal toxicity and post-operative nausea and vomiting. Limited data exists to support the optimal regimen for HIPEC at the time of CRS in women with EOC. From our experience, we favor use of cisplatin 100 mg/m2 alone or in combination with paclitaxel 135-175 mg/m2 with 90 min of total perfusion time. Close attention to temperature and glycemic control is essential during the procedure, as electrolyte derangements including hyperglycemia, lactic acidosis and hypokalemia may occur. Continuous patient monitoring and proactive management of abnormalities that arise during HIPEC is imperative to decrease patient morbidity and mortality.

Management of genitourinary syndrome of menopause in female cancer patients: a focus on vaginal hormonal therapy.

Genitourinary syndrome of menopause is a condition describing the hypoestrogenic effects on the female genitals and lower urinary tract leading to symptoms such as vaginal dryness, vulvar and vaginal burning, dyspareunia and dysuria. Genitourinary syndrome of menopause is experienced by over half of postmenopausal women, and is even more pervasive in women with cancer. Due to treatments such as surgery, chemotherapy, radiation, and hormonal therapy, women may experience early menopause resulting in earlier and more severe symptoms. Understanding the scope of this issue in female breast and gynecologic cancer survivors and identifying treatment options for this complex patient population are paramount. Tailored patient treatments include nonhormonal therapies (vaginal moisturizers, lubricants, pelvic floor physical therapy, dilator therapy, counseling), systemic and local hormonal therapies. Consensus recommendations by medical societies and associated evidence are reviewed, with emphasis on safety and efficacy of local vaginal hormonal therapies, and management variations noted depending on cancer type and characteristics. With knowledge and understanding of the unmet need associated with under-recognition and under-treatment of genitourinary syndrome of menopause, providers caring for women with cancer are in a position to improve the quality of life of their patients by providing safe and effective treatments.

Thy-1 predicts poor prognosis and is associated with self-renewal in ovarian cancer.

BACKGROUND: Ovarian cancer is the leading cause of gynecologic cancer death in the United States despite effective first-line systemic chemotherapy. Cancer stem cells (CSCs) retain the ability to self-renew and proliferate and may be a means of harboring disease that evades standard treatment strategies. We previously performed a high-throughput screen to assess differential protein expression in ovarian CSCs compared to non-CSCs and observed that Thy-1 was more highly expressed in CSCs. Our primary aim was to validate Thy-1 (CD90) as a cancer stem cell (CSC) marker in epithelial ovarian cancer (EOC), correlate with clinical outcomes, and assess as a potential therapeutic target. RESULTS: Kaplan Meier (KM) Plotter data were correlated with survival outcomes. Quantitative real-time PCR, flow cytometry, and immunoblots assessed RNA and protein expression. Limiting dilution assays assessed self-renewal capacity and proliferation assays assessed proliferative capacity. RNA in-situ hybridization was performed on patient specimens to assess feasibility. Thy-1 (CD90) is more highly expressed in ovarian CSCs than non-CSCs, in EOC compared to benign ovarian epithelium (P < 0.001), and is highest in serous EOC (P < 0.05). Serous ovarian cancers with high Thy-1 expression have poorer outcomes (median PFS 15.8 vs. 18.3 months, P = 0 < 0.001; median OS 40.1 v. 45.8 months, P = 0.036). Endometrioid ovarian cancers with high Thy-1 have poorer PFS, but no difference in OS (upper quartile PFS 34 v. 11 months, P = 0.013; quartile OS not reached, P = 0.69). In vitro, Thy-1 expression is higher in CSCs versus non-CSCs. EOC cells with high Thy-1 expression demonstrate increased proliferation and self-renewal. Thy-1 knockdown in EOC cells decreases proliferative capacity and self-renewal capacity, and knockdown is associated with decreased expression of stem cell transcription factors NANOG and SOX2. RNA in situ hybridization is feasible in ovarian cancer tissue specimens. CONCLUSIONS: Thy-1 is a marker of ovarian CSCs. Increased expression of Thy-1 in EOC predicts poor prognosis and is associated with increased proliferative and self-renewal capacity. Thy-1 knockdown decreases proliferative and self-renewal capacity, and represents a potential therapeutic target.

Leptin Regulation of Cancer Stem Cells in Breast and Gynecologic Cancer.

It is well established that obesity increases the incidence and worsens the prognosis of women's cancer. For breast cancer, women with obesity exhibit more than a twofold increase in the odds of being diagnosed with cancer, with a greater risk of advanced stage at diagnosis, and ≤40% greater risk of recurrence and death than their normal-weight counterparts. These findings are similar in gynecologic cancers, where women who are obese with a body mass index (BMI) >40 kg/m2 have up to six times greater risk of developing endometrial cancer and a 9.2% increase in mortality with every 10% increase in BMI. Likewise, patients with obesity exhibit a twofold higher risk of premenopausal ovarian cancer, and patients who are obese with advanced stage ovarian cancer have shown a shorter time to recurrence and poorer overall survival. Obesity is accompanied by changes in expression of adipose factors that act on local tissues and systemically. Once obesity was recognized as a factor in cancer incidence and progression, the adipose cytokine (adipokine) leptin became the focus of intense investigation as a putative link, with nearly 3000 publications on the topic. Leptin has been shown to increase cell proliferation, inhibit apoptosis, promote angiogenesis, and increase therapeutic resistance. These characteristics are associated with a subset of cells in both liquid and solid tumors known as cancer stem cells (CSCs), or tumor initiating cells. We will review the literature discussing leptin's role in breast and gynecologic cancer, focusing on its role in CSCs, and consider goals for targeting future therapy in this arena to disrupt tumor initiation and progression in women's cancer.